Our goal is to develop novel small molecule antagonists of tau filament formation. Such molecules are expected to be useful therapeutic agents capable of halting the formation of a hallmark pathology common to Alzheimer's disease and other dementias. There are three specific Aims. First, using an established high-throughput screening method, small molecule antagonists of tau filament formation will be identified. Second, inhibitory activity will be confirmed using secondary screens. In addition, inhibitory activity will be demonstrated against all human tau isoforms found in the central nervous system. Third, the ability of lead inhibitors to disassemble existing filaments will be examined using both synthetic and authentic, Alzheimer's disease derived, tau filaments. Successful completion of these Phase I studies will lead to the identification of small molecules capable of arresting filament formation, regardless of tau isoform involved, in a manner that does not poison normal microtubule function. These experiments also will define appropriate candidates for Phase II studies, where biological activity and toxicity will be assessed. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE